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Department of Anaesthesiology and Intensive Care, Salzburger Landeskliniken SALK, 48 Mullner Hauptstrasse, 5020 Salzburg, Austria
Department of Anaesthesia, University Hospital of Wales, Cardiff, UK
3
Department of Haematology, School of Medicine, Cardiff University, Cardiff, UK
2
Summary. Postpartum haemorrhage (PPH) is a major risk factor for maternal morbidity and
mortality. PPH has numerous causative factors, which makes its occurrence and severity
difficult to predict. Underlying haemostatic imbalances such as consumptive and
dilutional coagulopathies may develop during PPH, and can exacerbate bleeding and lead
to progression to severe PPH. Monitoring coagulation status in patients with PPH may be
crucial for effective haemostatic management, goal-directed therapy, and improved
outcomes. However, current PPH management guidelines do not account for the altered
baseline coagulation status observed in pregnant patients, and the appropriate
transfusion triggers to use in PPH are unknown, due to a lack of high-quality studies
specific to this area. In this review, we consider the evidence for the use of standard
laboratory-based coagulation tests and point-of-care viscoelastic coagulation monitoring
in PPH. Many laboratory-based tests are unsuitable for emergency use due to their long
turnaround times, so have limited value for the management of PPH. Emerging evidence
suggests that viscoelastic monitoring, using thrombelastography- or thromboelastometrybased tests, may be useful for rapid assessment and for guiding haemostatic therapy
during PPH. However, further studies are needed to define the ranges of reference values
that should be considered normal in this setting. Improving awareness of the correct
application and interpretation of viscoelastic coagulation monitoring techniques may be
critical in realizing their emergency diagnostic potential.
Keywords: blood coagulation tests; point-of-care systems; postpartum haemorrhage;
thrombelastography
thrombin generation, may be the major coagulation abnormality associated with obstetric bleeding.12 15 Similar observations have been made during blood loss in trauma16 and
major surgery.17
The diversity of potential triggers makes the occurrence
and severity of PPH difficult to predict. Many cases have no
identifiable risk factor.3 However, episodes of PPH with differing causes may have common pathological progression, with
measurement of haemostatic impairment potentially providing important information for diagnosis and therapeutic
intervention. Bleeding leads to loss and consumption of coagulation factors, which may be exacerbated by dilutional
coagulopathy after volume resuscitation. Coagulation
defects may be compounded by hyperfibrinolysis. Rapid correction of coagulopathies that develop during PPH may be
crucial for controlling bleeding and improving outcomes.
However, appropriate haemostatic intervention may
depend on the availability of tests which allow rapid diagnosis of the cause of bleeding. In this review, we discuss the
normal changes in clotting factors during pregnancy, the importance of coagulation failure during major PPH, tests that
& The Author [2012]. Published by Oxford University Press on behalf of British Journal of Anaesthesia. This is an Open Access article distributed
under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial
reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
BJA
Solomon et al.
TONE
TISSUE
Placental complications
Placenta praevia
placental blockage of cervix
Placental abruption
e.g. chorioamnionitis
TRAUMA
THROMBIN
Physical injury
Acquired coagulopathy
e.g. DIC, hyperfibrinolysis,
pharmacologic anticoagulation
Uterine rupture
Previous trauma
Grand multiparity
Previous vertical uterine incision
Fig 1 Major risk factors associated with PPH. Conditions are classified according to pathophysiology. DIC, disseminated intravascular coagulation; vWD, von Willebrands disease; PPH,
postpartum haemorrhage.
are available for monitoring haemostasis, and the implications of coagulation monitoring for PPH management
strategies.
Methodology
We conducted a literature search for articles describing
haemostasis testing/coagulation monitoring in the obstetric
setting, using PubMed with the following search terms with
no filters applied: [blood coagulation tests (MeSH)] and obstetric; [thrombelastography (MeSH)] and obstetric; [blood
coagulation tests (MeSH)] and [peripartum period (MeSH)];
[thrombelastography (MeSH)] and [peripartum period
(MeSH)]; [blood coagulation tests (MeSH)] and [postpartum
hemorrhage (MeSH)]; [thrombelastography (MeSH)] and
[postpartum hemorrhage (MeSH)]; [postpartum hemorrhage
(MeSH)] and [Blood coagulation (MeSH)]; [postpartum hemorrhage (MeSH)] and [Blood coagulation factors (MeSH)]. In
total, 674 articles were retrieved. Articles published after
1991 were screened (abstract if available, whole article if
not) and retained if the use of laboratory coagulation tests,
point-of-care (POC) coagulation coagulation monitoring, or
measurement of individual coagulation factors/inhibitors
was reported during healthy pregnancy, obstetric complication, or PPH. After screening, 121 articles remained; these
formed the evidence-base for the review and included
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Pro-coagulation
Anti-coagulation
Fibrinogen
FVII
vWF
FX
FVIII
Increased
during
pregnancy
Coagulation inhibitors,
mediators and indicators of
clot breakdown
FXII
D-dimer
FIX
PAI-1
TAT complex
TAFI
Fibrinopeptide A
Prothrombin fragment 1 + 2
Variably
increase/decrease
or no overall change
Decreased
during
pregnancy
FV
FXIII
FXI
Protein C
Antithrombin
Protein S
Platelet count
tPA
Fig 2 Changes in haemostatic variables observed during normal, healthy pregnancy. The overall increase in pro-coagulant factors results in a
typically hypercoagulable state which increases throughout pregnancy. Increases and decreases are relative to non-pregnancy. Positioning of
factors is not indicative of the precise level of increase or decrease. FV, Factor V; FVII, Factor VII; FVIII, Factor VIII; FIX, Factor IX; FX, Factor X;
FXI, Factor XI; FXII, Factor XII; FXIII, Factor XIII; PAI-1, plasminogen activator inhibitor 1; TAFI, thrombin activatible fibrinolysis inhibitor; TAT
complex, thrombin antithrombin complex; vWF, von Willebrand factor.
(e.g. placental abruption) is suspected. A comprehensive assessment of bleeding history and medication history is considered more accurate and cost-effective.25 30 33 35
If congenital haemostatic defects are suspected, tests
may be conducted to identify specific coagulation factor deficiencies, so that appropriate prophylactic treatments can be
incorporated into the plan for labour to minimize the risk of
PPH. Typically, these tests are performed at 28 34 weeks
gestation and should involve a multi-disciplinary team including a specialist in high-risk obstetrics and a haematologist.36 Guidelines have been published for the management
of obstetric patients with congenital bleeding disorders,36
37
although a lack of data for many of the rarer conditions
limits the possible recommendations specific to PPH. The
recommendations are based on treatment of non-pregnant
individuals, so do not account for the altered baseline coagulation status in pregnancy. To determine the true utility of
853
BJA
genital tract bleeding.8 14 This again raises the question of
what the appropriate target fibrinogen level should be
during ongoing PPH and whether this should differ from
other causes of massive haemorrhage. Current PPH management guidelines3 recommend maintaining PT and aPTT at
1.5 times normal control values, platelet count at
50109 litre21, and plasma fibrinogen at 1 g litre21, identical to the recommendations for non-pregnant
populations.37
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Solomon et al.
These findings suggest that platelet transfusion or desmopressin may be valid haemostatic therapies for PPH.
However, they raise concerns about recommended transfusion triggers. Data suggest that platelet count should be
maintained 100109 litre21 during ongoing PPH,15 but a
prospective analysis of 30 patients with coagulopathy after
abruptio placentae had platelet counts 90109 litre21 at
0 and 4 h postpartum.48 However, current PPH guidelines recommend platelet transfusion only when the platelet count
decreases below 50109 litre21,3 although in other
massive haemorrhage guidelines, a trigger of 75109
litre21 is recommended.49 Studies are required to confirm
the validity of current approaches.
BJA
molecular size; 50% haemodilution resulted in greater fibrinogen overestimation than 30% dilution. Compared with
haemodilution using isotonic saline or albumin, HES also
decreases fibrin-based clot firmness measured using thromboelastometry.69 Thus, HES provides a twin hazard by compromising clot quality while over-representing plasma
fibrinogen.
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Solomon et al.
A
mm
mm
CT
60
A15
40
20
A20
60
MCF
40
A10
20
A5
20
20
40
40
60
60
10
20
30
40
50 min
10
20
30
40
EXTEM
50 min
FIBTEM
mm
mm
60
60
40
40
20
20
20
20
40
40
60
60
10
20
30
40
50 min
10
20
EXTEM
30
40
50 min
FIBTEM
C
mm
60
MA
40
20
20
40 r k
60
10
20
30
40
50 min
Fig 3 ROTEMw- and TEGw-based coagulation profiles in the peripartum period. Schematic representation of healthy (A) and coagulopathic (B)
obstetric coagulation profiles for EXTEM and FIBTEM tests. Coagulation parameters which are typically reported for these tests are indicated in
the top-left panel. The profiles reflect EXTEM and FIBTEM test results reported for healthy patients around the time of delivery,29 38 87 and for
patients with PPH associated with poor fibrin-clot quality.13 90 Clot lysis parameters are not indicated; if (hyper)fibrinolysis is suspected, an
APTEM test can be performed. APTEM profiles mirror EXTEM profiles under healthy conditions, and show enhanced coagulation vs EXTEM
during fibrinolysis.76 Also presented (C) is a healthy, obstetric coagulation profile for kaolin-activated thrombelastography, with typically
reported parameters indicated for this test. The profile reflects kaolin-TEGw values observed for healthy patients in the third trimester,86
and before elective Caesarean delivery.114 Owing to the lack of available evidence for typical test results, profiles are not presented for kaolinTEGw during PPH, or for other TEGw-based tests in obstetric patients. a8, alpha angle; A5 A20, clot amplitude at 520 min after CT; CT, clotting
time; MA, maximum amplitude; MCF, maximum clot firmness; PPH, postpartum haemorrhage; r, reaction time.
the diagnostic utility of each assay in different clinical situations, may be critical for correct, timely diagnosis of coagulopathy during haemorrhage.
856
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Table 1 Parameters recordable using TEGw and ROTEMw-based tests. *G(5000MA)/(1002MA);127 MCE(100MA)/(1002MA)130
Parameter recorded
TEGw value
ROTEMw value
Description
Coagulation initiation
r (reaction time)
CT (clotting time)
Clot formation
k
a8 (alpha angle)
Clot strength/quality
Clot lysis
MA (maximum amplitude)
G (clot rigidity)
LY30 (lysis)
Table 2 Commercially available TEGw- and ROTEMw-based coagulation tests. Analogous tests for the different devices are presented
side-by-side in the same row. Details of the assay principles and applications of TEGw-based tests can be found at http://www.haemonetics.com/
site/pdf/teg-product-brochure.pdf. Similar details for ROTEMw-based tests are available at http://www.rotem.de/site/. *Tests are typically
performed using recalcified, citrated blood. FII, factor; FV, factor V; FVIII, factor VIII; FIX, factor IX; FXI, factor XI; FXII, factor XII; FF, functional
fibrinogen
TEGw-based tests
ROTEMw-based tests
Diagnostic use
Test (reagent
name)
Activator
Additional
modifications*
Test
(reagent
name)
Activator
Additional
modifications*
NATEM
(star-temw)
None added
Kaolin-activated
TEGw
Kaolin
INTEM
(in-temw)
Ellagic acid
EXTEM
(ex-temw)
Recombinant
tissue factor
RapidTEG
(RapidTEGTM
reagent)
Kaolin + tissue
factor
FF/functional
fibrinogen test (FF
reagent)
Tissue factor
Abciximab
FIBTEM
(fib-temw)
Recombinant
tissue factor
Cytochalasin D
APTEM
(ap-temw)
Recombinant
tissue factor
Aprotinin
Kaolin-activated
TEGw + heparinase
Kaolin
Heparinase
HEPTEM
(hep-temw)
Ellagic acid
Heparinase
Heparin/protamine imbalance
(in conjunction with INTEM or
kaolin-activated TEG)
This corroborated an earlier study83 which demonstrated significant differences in TEGw-recorded r, k, a8, and MA values
between healthy non-labouring pregnant women and nonpregnant women, and a later study establishing TEGw-based
reference ranges in parturients undergoing Caesarean
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section with spinal anaesthesia.84 ROTEMw-based analysis
has shown that hypercoagulability is not limited to the predelivery period; low CT and CFT, and elevated a8, A20, and
MCF, can persist up to 3 weeks postpartum.85 These data
again highlight the importance of establishing reference
ranges for TEGw/ROTEMw-recordable parameters in pregnant
women.13 29 38 86 87
When attempting to use coagulation status to predict
PPH, it is important to remember that, unlike many clinical
settings, substantial blood loss may be considered normal
in obstetric patients. Blood loss of 500 ml may occur before
PPH is suspected and up to 1000 ml may be tolerated in
women without underlying medical disorders.88 It can be
argued that baseline assessment of haemostatic activity
postpartum should not be measured pre-delivery, but
instead taken after 500 1000 ml blood loss. Assessment of
coagulation dynamics after this initial bleed may provide a
more reliable indication of coagulation abnormalities which
may develop postpartum, and thus may better reflect the
risk of imminent progression to PPH.
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Solomon et al.
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similar diagnosis to EXTEM and FIBTEM. However, the diagnostic performances of FIBTEM and FF differ,110 so further
validation of the FF test is required. The argument for using
MCE over MCF in ROTEM analysis also applies to using clot rigidity (G) in place of MA for TEGw-based tests.127
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BJA
Owing to the lack of studies directly relating to PPH, much
of the data covered in this review are necessarily extrapolated from other settings, such as trauma or cardiac
surgery. However, not all massive haemorrhage is the
same, and the haemostatic derangements seen in these settings are likely to differ from those in PPH. High-quality
studies are needed to examine these differences. Current
PPH management guidelines do not account for the altered
baseline coagulation status in obstetric patients. Future
studies should address the need for reference values and
triggers for haemostatic therapy in patients with PPH. POC
tests are more suitable in PPH due to their faster turnaround
time. By improving awareness of the correct application and
interpretation of these tests, we can make better use of their
emergency diagnostic capabilities and increase our understanding of the most appropriate haemostatic interventions
for the management of obstetric bleeding. Data regarding
the efficacy of haemostatic therapies in PPH are sparse.
Studies of fibrinogen replacement therapies should be prioritized, as decreasing fibrinogen levels have been linked with
PPH progression.
Declaration of interest
The authors have the following conflicts of interests to
declare: C.S. has received travel support from Haemoscope
Ltd (former manufacturer of TEGw), and speaker honoraria
and/or research support from Tem International and CSL
Behring. R.E.C. has received speaker honoraria from CSL
Behring and Novo Nordisk and research support from Tem
International. P.W.C. has received speaker honoraria from
CSL Behring and Novo Nordisk and research support from
Tem International.
Solomon et al.
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Funding
20
Editorial assistance with manuscript preparation was provided by Meridian HealthComms, funded by CSL Behring.
Funding to pay the Open Access publication charges for
this article was provided by CSL Behring.
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